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Chapter 182. Human Immunodeficiency Virus Disease: AIDS and Related Disorders  Introduction AIDS was first recognized in the United States in the summer of 1981, when the U.S. Centers for Disease Control and Prevention (CDC) reported the unexplained occurrence of Pneumocystis jiroveci (formerly P. carinii) pneumonia in five previously healthy homosexual men in Los Angeles and of Kaposi's sarcoma (KS) with or without P. jiroveci pneumonia in 26 previously healthy homosexual men in New York and Los Angeles. Within months, the disease became recognized in male and female injection drug users (IDUs) and soon thereafter in recipients of blood transfusions and in hemophiliacs. As the epidemiologic pattern of the disease unfolded, it became clear that an infectious agent transmissible by sexual (homosexual and heterosexual) contact and blood or blood products was the most likely etiologic cause of the epidemic. In 1983, human immunodeficiency virus (HIV) was isolated from a patient with lymphadenopathy, and by 1984 it was demonstrated clearly to be the causative agent of AIDS. In 1985, a sensitive enzyme-linked immunosorbent assay (ELISA) was developed, which led to an appreciation of the scope and evolution of the HIV epidemic at first in the United States and other developed nations and ultimately among developing nations throughout the world (see below). The staggering worldwide evolution of the HIV pandemic has been matched by an explosion of information in the areas of HIV virology, pathogenesis (both immunologic and virologic), treatment of HIV disease, treatment and prophylaxis of the opportunistic diseases associated with HIV infection, prevention of infection, and vaccine development. The information flow related to HIV disease is enormous and continues to expand, and it has become almost impossible for the health care generalist to stay abreast of the literature. The purpose of this chapter is to present the most current information available on the scope of the epidemic; on its pathogenesis, treatment, and prevention; and on prospects for vaccine development. Above all, the aim is to provide a solid scientific basis and practical clinical guidelines for a state-of-the-art approach to the HIV-infected patient. Definition The current CDC classification system for HIV-infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte counts. The system is based on three ranges of CD4+ T lymphocyte counts and three clinical categories and is represented by a matrix of nine mutually exclusive categories (Tables 182-1 and 182-2). Using this system, any HIV-infected individual with a CD4+ T cell count of <200/µL has AIDS by definition, regardless of the presence of symptoms or opportunistic diseases (Table 182-1). Once individuals have had a clinical condition in category B, their disease classification cannot be reverted back to category A, even if the condition resolves; the same holds true for category C in relation to category B. Table 182-1 1993 Revised Classification System for HIV Infection and Expanded AIDS Surveillance Case Definition for Adolescents and Adultsa Clinical Categories CD4+ T Cell A Asymptomatic, B Symptomatic, Categories Acute (Primary) HIV Not A or C or PGLb Conditions C AIDSIndicator Conditions >500/µL 200–499/µL <200/µL C1 C2 C3 A1 A2 A3 B1 B2 B3 a The shaded areas indicate the expanded AIDS surveillance case definition. PGL, progressive generalized lymphadenopathy. Source: MMWR 42(No. RR-17), December 18, 1992. b  Table 182-2 Clinical Categories of HIV Infection Category A: Consists of one or more of the conditions listed below in an adolescent or adult (>13 years) with documented HIV infection. Conditions listed in categories B and C must not have occurred. Asymptomatic HIV infection Persistent generalized lymphadenopathy Acute (primary) HIV infection with accompanying illness or history of acute HIV infection Category B: Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical category C and that meet at least one of the following criteria: (1) The conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or (2) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples include, but are not limited to, the following: Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting >1 month Hairy leukoplakia, oral Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tuboovarian abscess Peripheral neuropathy Category C: Conditions listed in the AIDS surveillance case definition. Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal Cervical cancer, invasivea Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month's duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (>1 month's duration); or bronchitis, pneumonia, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month's duration) Kaposi's sarcoma Lymphoma, Burkitt's (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonarya or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrenta Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV a Added in the 1993 expansion of the AIDS surveillance case definition. Source: MMWR 42(No. RR-17), December 18, 1992.  The definition of AIDS is indeed complex and comprehensive and was established not for the practical care of patients, but for surveillance purposes. Thus, the clinician should not focus on whether or not the patient fulfills the strict definition of AIDS, but should view HIV disease as a spectrum ranging from primary infection, with or without the acute syndrome, to the asymptomatic stage, to advanced disease (see below). Etiologic Agent The etiologic agent of AIDS is HIV, which belongs to the family of human retroviruses (Retroviridae) and the subfamily of lentiviruses (Chap. 181). Nononcogenic lentiviruses cause disease in other animal species, including sheep, horses, goats, cattle, cats, and monkeys. The four recognized human retroviruses belong to two distinct groups: the human T lymphotropic viruses (HTLV)-I and HTLV-II, which are transforming retroviruses; and the human immunodeficiency viruses, HIV-1 and HIV-2, which cause cytopathic effects either directly or indirectly (see below and Chap. 181). The most common cause of HIV disease throughout the world, and certainly in the United States, is HIV-1, which comprises several subtypes with different geographic distributions (see below). HIV-2 was first identified in 1986 in West African patients and was originally confined to West Africa. However, a number of cases that can be traced to West Africa or to sexual contacts with West Africans have been identified throughout the world. Both HIV-1 and HIV-2 are zoonotic infections. The Pan troglodytes troglodytes species of chimpanzees has been established as the natural reservoir of HIV-1 and the most likely source of original human infection. HIV-2 is more closely related phylogenetically to the simian immunodeficiency virus (SIV) found in sooty mangabeys than it is to HIV1. The taxonomic relationship among primate lentiviruses is shown in Fig. 182-1. Figure 182-1 A phylogenetic tree, based on the complete genomes of primate immunodeficiency viruses. The scale at the bottom (0.10) indicates a 10% difference at the nucleotide level. (Prepared by Brian Foley, PhD, of the HIV Sequence Database, Theoretical Biology and Biophysics Group, Los Alamos National Laboratory.)  Morphology of HIV Electron microscopy shows that the HIV virion is an icosahedral structure (Fig. 182-2A) containing numerous external spikes formed by the two major envelope proteins, the external gp120 and the transmembrane gp41. The virion buds from the surface of the infected cell and incorporates a variety of host proteins, including major histocompatibility complex (MHC) class I and II antigens (Chap. 309), into its lipid bilayer. The structure of HIV-1 is schematically diagrammed in Fig. 182-2B (Chap. 181). Figure 182-2 A. Electron micrograph of HIV. Figure illustrates a typical virion following budding from the surface of a CD4+ T lymphocyte, together with two additional incomplete virions in the process of budding from the cell membrane. B. Structure of HIV-1, including the gp120 outer membrane, gp41 transmembrane components of the envelope, genomic RNA, enzyme reverse transcriptase, p18(17) inner membrane (matrix), and p24 core protein (capsid) (copyright by George V. Kelvin). (Adapted from RC Gallo: Sci Am 256:46, 1987.)  Replication Cycle of HIV HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with the high-affinity binding of the gp120 protein via a portion of its V1 region near the N terminus to its receptor on the host cell surface, the CD4 molecule (Fig. 182-3). The CD4 molecule is a 55-kDa protein found predominantly on a subset of T lymphocytes that are responsible for helper function in the immune system (Chap. 308). It is also expressed on the surface of monocytes/macrophages and dendritic/Langerhans cells. Once gp120 binds to CD4, the gp120 undergoes a conformational change that facilitates binding to one of a group of coreceptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both receptors belong to the family of seven-transmembrane-domain G protein–coupled cellular receptors, and the use of one or the other or both receptors by the virus for entry into the cell is an important determinant of the cellular tropism of the virus (see below for details). Certain dendritic cells express a diversity of C-type lectin receptors on their surface, one of which is called DC-SIGN, that also bind with high affinity to the HIV gp120 envelope protein, allowing the dendritic cell to facilitate the binding of virus to the CD4+ T cell upon engagement of dendritic cells with CD4+ T cells. Following binding of the envelope protein to the CD4 molecule associated with the above-mentioned conformational change in the viral envelope gp120, fusion with the host cell membrane occurs via the newly exposed gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion and target cell together. Following fusion, the preintegration complex, composed of viral RNA and viral enzymes and surrounded by a capsid protein coat, is released into the cytoplasm of the target cell (Fig. 182-4). As the preintegration complex traverses the cytoplasm to reach the nucleus (Fig. 182-3), the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, and the protein coat opens to release the resulting doublestranded HIV-DNA. At this point in the replication cycle, the viral genome is vulnerable to cellular factors that can block the progression of infection. In particular, the cytoplasmic TRIM5-α protein in rhesus macaque cells blocks SIV replication at a point shortly after the virus fuses with the host cell. Although the exact mechanisms of action of TRIM5-α remain unclear, the human form is inhibited by cyclophilin A and is not effective in restricting HIV replication in human cells. The recently described APOBEC family of cellular proteins also inhibits progression of virus infection after virus has entered the cell. APOBEC proteins bind to nascent reverse transcripts and deaminate viral cytidine, causing hypermutation of HIV genomes. It is still not clear whether (1) viral replication is inhibited by the binding of APOBEC to the virus genome with subsequent accumulation of reverse transcripts, or (2) by the hypermutations caused by the enzymatic deaminase activity of APOBEC proteins. HIV has evolved a powerful strategy to protect itself from APOBEC. The viral protein Vif targets APOBEC for proteasomal degradation. Figure 182-3 The replication cycle of HIV. See text for description. (Adapted from Fauci, 1996.)  Figure 182-4 Binding and fusion of HIV-1 with its target cell. HIV-1 binds to its target cell via the CD4 molecule, leading to a conformational change in the gp120 molecule that allows it to bind to the co-receptor CCR5 (for R5using viruses). The virus then firmly attaches to the host cell membrane in a coiled-spring fashion via the newly exposed gp41 molecule. Virus-cell fusion occurs as the transitional intermediate of gp41 undergoes further changes to form a hairpin structure that draws the two membranes into close proximity (see text for details). (Adapted from D Montefiori, JP Moore: Science 283:336, 1999; with permission.)  With activation of the cell, the viral DNA accesses the nuclear pore and is exported from the cytoplasm to the nucleus, where it is integrated into the host cell chromosomes through the action of another virally encoded enzyme, integrase. HIV provirus (DNA) selectively integrates into the nuclear DNA preferentially within introns of active genes and regional hotspots. This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression, up to active production of virus. Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogenesis of HIV disease (see below). Following initial binding and internalization of virions into the target cell, incompletely reverse-transcribed DNA intermediates are labile in quiescent cells and do not integrate efficiently into the host cell genome unless cellular activation occurs shortly after infection. Furthermore, some degree of activation of the host cell is required for the initiation of transcription of the integrated proviral DNA into either genomic RNA or mRNA. This latter process may not necessarily be associated with the detectable expression of the classic cell surface markers of activation. In this regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristylation, phosphorylation, and cleavage. The viral particle is formed by the assembly of HIV proteins, enzymes, and genomic RNA at the plasma membrane of the cells. Budding of the progeny virion occurs through specialized regions in the lipid bilayer of the host cell membrane known as lipid rafts, where the core acquires its external envelope (Chap. 181). The virally encoded protease then catalyzes the cleavage of the gag-pol precursor (see below) to yield the mature virion. Progression through the virus replication cycle is profoundly influenced by a variety of viral regulatory gene products. Likewise, each point in the replication cycle of HIV is a real or potential target for therapeutic intervention (see below). Thus far, the reverse transcriptase, protease, and integrase enzymes as well as the process of virus–target cell binding and fusion have proven clinically to be susceptible to pharmacologic disruption (see below). Inhibitors of the maturation process of virions during the latter phase of the replication cycle are currently being evaluated in clinical trials. HIV Genome Figure 182-5 illustrates schematically the arrangement of the HIV genome. Like other retroviruses, HIV-1 has genes that encode the structural proteins of the virus: gag encodes the proteins that form the core of the virion (including p24 antigen); pol encodes the enzymes responsible for protease processing of viral proteins, reverse transcription, and integration; and env encodes the envelope glycoproteins. However, HIV-1 is more complex than other retroviruses, particularly those of the nonprimate group, in that it also contains at least six other genes (tat, rev, nef, vif, vpr, and vpu), which code for proteins involved in the modification of the host cell to enhance virus growth and the regulation of viral gene expression (Chap. 181). Several of these proteins are thought to play a role in the pathogenesis of HIV disease; their various functions are listed in Fig. 182-5. Flanking these genes are the long terminal repeats (LTRs), which contain regulatory elements involved in gene expression (Fig. 182-5). The major difference between the genomes of HIV-1 and HIV-2 is the fact that HIV-2 lacks the vpu gene and has a vpx gene not contained in HIV-1. Figure 182-5